1. Field of the Invention
This invention relates to a process for preparing amorphous solid macrolide antibiotics which are stable with the passage of a long period of time.
2. Description of the Prior Art
A substance which is sparingly soluble in water generally has the property that crystals thereof differ in solubility from the amorphous solid form thereof, and the latter has a higher solubility. This difference in solubility is of great significance in pharmaceutical formulations. For example, macrolide antibiotics (e.g., midecamycin, kitasamycin, josamycin, erythromycin, spiramycin, or derivatives thereof) are sparingly water soluble substances, and in orally administrable formulations such as tablets, capsules or dry syrups of these substances, the use of the amorphous solid form thereof having better solubility, can lead to full effectiveness of these antibiotics.
Since, however, amorphous solids are inherently at a high energy level, they are unstable and apt to change into the crystal form with the passage of time. For example, the Japanese language publication "Method of Designing Pharmaceutical Formulations (2), First Part" (Lectures in Fundamentals of Development of Pharmaceuticals, Vol. IX, edited by Masashi Nogami and Kyosuke Tsuda, published by Chijin Shokan) states:
"Amorphous solids frequently assume this state by lyophilization, rapid cooling of a molten liquid, or the co-presence of impurities (a kind of plasticization), but are apt to be converted to a stable crystalline state."
Attempts to obtain amorphous solids of macrolide antibiotics (e.g., midecamycin, 9-acetyl-3"-acetylmidecamycin, kitasamycin, erythromycin, or josamycin) by ordinary techniques (e.g., lyophilization or the rapid cooling of a molten liquid) result in products containing crystals, or products which are readily converted to crystals with the passage of time, and it is difficult to obtain crystal-free amorphous solids which are stable with the passage of time.
Conventional techniques for the spray drying of macrolide antibiotics are disclosed, for example, in Japanese patent Applications (OPI) Nos. 81526/74, 133513/74 and 132216/74.
Japanese patent application (OPI) No. 81526/74 discloses a process for preparing a coated antibiotic for oral administration free from a bitter taste and a reduction in its effective concentration in blood which comprises dissolving a macrolide antibiotic in a solution or dispersion in an inert volatile organic solvent of a wall forming polymer selected from the group consisting of polyvinyl acetal diethylaminoacetate, cellulose acetate dibutylaminohydroxypropyl ether, a dimethylaminoethyl methacrylate/methacrylate copolymer and ethyl cellulose and at least one material selected from the group consisting of waxes, higher fatty acids and insoluble salts of higher fatty acids, and spray drying the resulting solution.
Japanese patent application (OPI) No. 133513/74, on the other hand, discloses a process for preparing a coated antibiotic for oral administration free from a bitter taste and a reduction in its effective concentration in blood which has a fine particle size and excellent water repellency, which comprises dissolving the macrolide antibiotic in a solution or dispersion in the above organic solvent of the wall forming polymer and at least one material selected from higher fatty acids, waxes, and insoluble salts of higher fatty acids and also a non-toxic mineral oil, vegetable oil, animal oil, surfactant or defoamer soluble in the above organic solvent and having an H.L.B. of not more than about 5, and spray drying the resulting solution.
Furthermore, Japanese patent application (OPI) No. 132216/74 discloses a process for producing a coated macrolide antibiotic suitable for oral administration which has a good shape and is free from bitterness and a reduction in its concentration in blood, the process comprising dissolving a macrolide antibiotic in a solution or dispersion in an inert volatile organic solvent of a wall forming material selected from the group consisting of a styrene/maleic acid copolymer, higher fatty acids, higher fatty acid derivatives and water insoluble salts of higher fatty acids, and spray drying the resulting solution.
The invention of Japanese patent application (OPI) No. 81526/74 requires at least one coating substance selected from the group of wall forming polymers and the group of waxes, higher fatty acids and insoluble salts of higher fatty acids.
In the invention of Japanese patent application (OPI) No. 133513/74, a non-toxic mineral oil, vegetable oil, animal oil, surfactant or defoamer having an H.L.B. of not more than about 5 is further used as a coating material in addition to the coating material used in the invention of Japanese patent application No. (OPI) 81526/74.
The invention of Japanese patent application (OPI) No. 132216/74 is the same as that of Japanese patent application (OPI) No. 81526/74 except that a styrene/maleic acid copolymer is used as the wall forming polymer. The amount of such coating substances is equal to, or larger than, that of the macrolide antibiotic, and they are regarded as effective for the prevention of the bitterness of the antibiotic.